Mechanism and therapy of AB-42-specific gamma-secretase

AB-42特异性γ-分泌酶的机制和治疗

基本信息

批准号：
8461609
负责人：
YUEMING LI
金额：
$ 54.04万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461609
关键词：
Address Adverse effects Affect Allosteric Site Alzheimer&apos s Disease Amino Acids Amyloid beta-Protein Precursor Animal Model Anti-Inflammatory Agents Anti-inflammatory Binding Binding Proteins Biochemical Biological Biological Models Biological Process Biology Cell model Cellular Assay Cellular biology Characteristics Chemicals Cleaved cell Clinical Trials Cognition Coumarins Development Drug Targeting Exhibits Generations Goals In Vitro Individual Investigation Kidney Knock-in Mouse Label Lead Learning Left Length Mediating Memory Metabolism Molecular Mechanisms of Action Molecular Probes Monitor Monophenol Monooxygenase Mus Neurons Neuropathogenesis Pathogenesis Pathway interactions Peptides Pharmaceutical Preparations Phase III Clinical Trials Physiological Play Process Production Property Protein Overexpression Proteins Proteomics Regulation Research Personnel Role Series Skin Neoplasms Skin Pigmentation Specificity Synaptic plasticity System Tertiary Protein Structure Testing Therapeutic Therapeutic Effect Treatment Efficacy alpha benzopyrone amyloid pathology amyloid precursor protein processing analog base efficacy testing gamma secretase in vivo inhibitor/antagonist innovation lysosomal proteins melanocyte mouse model mutant neuron development notch protein novel prevent protein transport public health relevance secretase synaptic function therapeutic development tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Due to the critical role of gamma-secretase in the generation of A? peptides, which are believed to be essential in Alzheimer's disease (AD) pathogenesis, gamma-secretase inhibitors have emerged as potential drug targets for AD. However, the wide spectrum of gamma-secretase substrates and the differential activities of the two major A? species, A?40 and A?42, in amyloid pathology have made gamma-secretase based therapy a formidable challenge. The combination of current understanding of the gamma-secretase biology with the recently failed clinical trial calls for the need to develop gamma-secretase inhibitors that specifically block A?42 production while leaving A?40 and other substrates intact. We have identified a series of compounds that exhibit these characteristics and they act through a distinct mechanism from that of A?42 gamma-secretase modulators. The overarching goal of this application is to elucidate the mechanism of action and therapeutic efficacy of A?42-specific gamma-secretase inhibition using an integrated approach of chemical biology, cell biology and animal models. We will develop a series of photoactivatable analogs to probe the molecular mechanisms of different mode of A?42 inhibition. We will determine their specificity and compare these with other classes of gamma-secretase inhibitors using novel cellular assays and in mice. Lastly, we will test the efficacy of A?42 specific inhibition on synaptic function and cognition in an AD knock-in mouse model. Overall, this proposal uses innovative approaches and model systems to address a topic highly significant in AD pathogenesis and therapeutic development.

描述（由申请人提供）：由于γ-分泌酶在A？的产生中的关键作用？肽被认为在阿尔茨海默病 (AD) 发病机制中至关重要，γ-分泌酶抑制剂已成为 AD 的潜在药物靶标。然而，γ-分泌酶底物的广谱性和两种主要 A? 的活性不同。淀粉样蛋白病理学中的 A?40 和 A?42 物种使基于 γ-分泌酶的治疗成为一项艰巨的挑战。目前对γ-分泌酶生物学的理解与最近失败的临床试验相结合，要求开发出特异性阻断Aβ42产生同时保持Aβ40和其他底物完整的γ-分泌酶抑制剂。我们已经鉴定了一系列表现出这些特征的化合物，并且它们通过与 Aβ42 γ-分泌酶调节剂不同的机制发挥作用。本申请的总体目标是利用化学生物学、细胞生物学和动物模型的综合方法阐明 Aβ42 特异性 γ 分泌酶抑制的作用机制和治疗功效。我们将开发一系列光激活类似物来探讨不同模式的Aβ42抑制的分子机制。我们将确定它们的特异性，并使用新型细胞测定法在小鼠中将其与其他类别的γ-分泌酶抑制剂进行比较。最后，我们将在AD敲入小鼠模型中测试Aβ42特异性抑制对突触功能和认知的功效。总体而言，该提案使用创新方法和模型系统来解决 AD 发病机制和治疗开发中非常重要的主题。